Design and synthesis of novel EGFR kinase inhibitors for the treatment of EGFR C797S mutation in non-small cell lung cancer

Third-generation cutaneous growth factor receptor tyrosine kinase inhibitors have led to impressive advances in the treatment of non-small cell lung cancer. However, acquired resistance significantly limits the clinical application of these agents, with the epidermal growth factor receptor (EGFR) ^C797S mutation being the primary resistance mechanism. In this study, a series of novel EGFR kinase inhibitors was designed and synthesized for the treatment of the EGFR ^C797S mutation in non-small cell lung cancer. Structure activity relationship screening revealed that compound 5d was the most effective inhibitor of the C797S mutation. It strongly inhibited Baf3-EGFR ^{L858R/T790M/C797S} and Baf3-EGFR ^{19del/T790M/C797S} cell lines, with IC ₅₀ values of 0.01836±0.0065 and 0.025±0.005 μM, respectively. Molecular docking studies showed that 5d binds to the EGFR ^{L858R/T790M/C797S} and EGFR ^{19del/T790M/C797S} proteins effectively. A mechanistic study showed that 5d induced cell cycle arrest in the G2/M phase. Compound 5d caused cell apoptosis in a dose-dependent manner, accompanied by a significant increase in the level of the apoptotic protein cleaved caspase-3. An in vivo xenograft assay of mice with Baf3-EGFR ^{19del/T790M/C797S} cells showed that 5d effectively inhibited tumor growth, with inhibition rates of 45.2% (70 mg/kg) and 55.7% (100 mg/kg) being observed. Therefore, 5d is worthy of further investigation as a fourth-generation EGFR inhibitor.